Action Points

This genetic study from a single Spanish hospital indicates that well-known FH clinical algorithms do not accurately identify and classify patients in this setting.

Familial hypercholesterolemia was often missed by clinical algorithms in a study, leading researchers to conclude that genetic screening during hospitalization for acute coronary syndrome (ACS) may be useful to identify young patients and family members at risk.

At one hospital, 8.7% of ACS patients with high LDL cholesterol levels had the autosomal dominant genetic disorder confirmed by genetic testing, according to Pablo Garcia-Pavia, MD, PhD, of Spain's Hospital Universitario Puerta de Hierro, and colleagues.

"This finding is much lower than the estimated familial hypercholesterolemia prevalence as determined by widely accepted clinical familial hypercholesterolemia criteria (27% in our cohort) but at the same time much higher than what has been previously reported in other familial hypercholesterolemia genetic screening studies," they wrote in the Journal of the American College of Cardiology.

These "disappointing" older screening studies had selected patients based solely on elevated LDL cholesterol and came out with a low detection rate of 2%.

In the present study, the prevalence of probable-to-definite familial hypercholesterolemia was 27.2% according to Dutch Lipic Clinic criteria and 27.2% per Simon Broome criteria. However, the two algorithms missed 44% and 33% of patients with genetically confirmed familial hypercholesterolemia, respectively, requiring cascade genetic testing in first-degree relatives to identify those individuals that fit the bill.

"Familial hypercholesterolemia clinical algorithms do not accurately classify patients with familial hypercholesterolemia. Genetic testing should be advocated in young patients with ACS and high LDL cholesterol levels to allow prompt identification of patients with familial hypercholesterolemia and relatives at risk," Garcia-Pavia's group concluded.

"Early recognition of familial hypercholesterolemia is essential because many patients with [the condition] are unaware of their disease, which is a major cause of early coronary heart disease. Identifying familial hypercholesterolemia allows specific counseling for diet and cardiovascular risk factors, and it ensures high-dose statin prescription and appropriate referral of family members for ... screening," they noted.

In an accompanying editorial, Joshua W. Knowles, MD, PhD, and Ashish Sarraju, MD, both of Stanford University, in Stanford, Calif., pointed out that 90% of people with familial hypercholesterolemia in the U.S. remain undiagnosed.

"As the cost of genetic testing continues to decrease and our knowledge of causal familial hypercholesterolemia variants improves, we look forward to future studies that validate these findings in larger ACS cohorts, so that others can be spared the fate of the unwitting canary in the coal mine," Knowles and Sarraju continued.

The investigators pointed out that the cost of FH next-generation sequencing genetic testing is now reasonable -- about 300-350 Euros or around $325-$375 -- "the cost-effective consequences of adopting a large-scale FH genetic screening program in patients with ACS following the criteria used in our study are unknown."

Garcia-Pavia's group offered genetic testing to ACS patients admitted at their institution (age ≤65 with LDL cholesterol at least 160 mg/dL). In total, 103 of those eligible accepted and most of them were white male patients, which was a study limitation, the authors acknowledged. None had a previous diagnosis of familial hypercholesterolemia.

Mean LDL cholesterol was 189.5 mg/dL at admission, and only 37.9% were on statins at the time.

Garcia-Pavia's group used next-generation sequencing to study the promoter, coding, and exon-intron boundary regions of five known culprit genes.

Among the seven families with a known pathogenic mutation that agreed to cascade screening, six of 21 relatives were diagnosed with familial hypercholesterolemia.

Additionally, the researchers noted that 29% without genetic markers for the condition had a genetic score -- based on 12 LDL-C–raising genetic variants -- consistent with polygenic hypercholesterolemia.

One year later, only one out of nine patients with genetically confirmed familial hypercholesterolemia had LDL cholesterol under the guideline-recommended 70 mg/dL (four were on ezetimibe plus a statin and three on suboptimal statin doses).

The study was funded by grants from the Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness, and Alexion.

Garcia-Pavia disclosed no relevant relationships with industry. Some co-authors disclosed being employees of Gendiag.exe/Ferrer inCode.

Knowles and Sarraju disclosed no relevant relationships with industry.

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